engleski

Carbamates of bronchodilators and Cinchona based alkaloids as selective BChE inhibitors

The inhibition of the BChE in human tissues is important for the detoxification and scavenging of xenobiotics such as organophosphates. Increased BChE activity in advanced AD, have led to the hypothesis that BChE needs to be inhibited to restore the brain levels of ACh. With an aim to evaluate preferable characteristic of novel potential therapeutics based on BChE inhibition with respect to AChE, we studied inhibition potency and selectivity of carbamates bearing the structural motif of bronchodilator bambuterol, a very selective BChE inhibitor, bronchodilators with a resorcinol-, catechol- and saligenin-containing structure and cinchonies and cinchonidines, quinine based alkaloids. All synthesised carbamates are potent and selective BChE inhibitors with carbamylation rates similar to that of bambuterol and inhibition potency dictated by the disposition of carbamate groups on the benzene ring, where meta-position is preferred over ortho-position. Both, AChE and BChE were stereoselective with an about five times higher preference for (R)- over (S)-carbamates. The studied bronchodilators reversibly inhibited AChE and BChE with inhibition potency depended to the size of the hydroxyaminoethyl chain on the benzene ring. Generally, studied bronchodilators have had higher preference to BChE without displaying any stereoselectivity. Furthermore, a series of 20 synthesised synthetic quaternary derivatives of cinchonidines and cinchonines reversibly inhibited BChE and AChE with inhibition constants in nanomolar to micromolar range and with a higher preference for BChE, up to 510 times higher inhibition selectivity toward BChE over AChE. The most selective and potent BChE inhibitor was cinchonidine with bromidium in para-position on benzene ring.

acetylcholinesterase ; butyrylcholinesterase ; inhibition potency ; steroselectivity

nije evidentirano